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Inosine, stroke and spinal cord injury.

Earlier studies from our lab showed that inosine, a metabolite of adenosine, acts through a direct intracellular mechanism to stimulate axon outgrowth from neurons in cell culture1. We went on to identify the target of insosine as Mst3b (STK24), a protein kinase that is an essential part of the cell-signaling pathway through which many trophic factors promote axon outgrowth in culture and in vivo2, 3. In vivo, we found that, after a unilateral stroke of the rat motor cortex, intraventricular delivery of inosine enhanced the ability of layer 5 pyramidal cells in the undamaged contralateral cortex to sprout axon collaterals into the denervated side of the spinal cord and improve skilled use of the impaired forepaw. This capacity was further enhanced by environmental enrichment or by combining inosine with a peptide antagonist of the Nogo receptor4, 5. Additional studies showed that inosine promotes the formation of “detour circuits” in the spinal cord after transecting the corticospinal tract (CST) at the mid-thoracic level. Inosine enhanced the ability of transected CST axons to sprout collateral branches in the cervical spinal cord that formed synaptic contacts onto spinal interneurons that project from the cervical spinal cord to the lumbar level, thus providing indirect cortical input to the lumbar spinal cord and restoring some volitional control to the hindlimbs6.

  1. Benowitz LI, Jing Y, Tabibiazar R, Jo SA, Petrausch B, Stuermer CA, Rosenberg PA, Irwin N. J Biol Chem Axon outgrowth is regulated by an intracellular purine-sensitive mechanism in retinal ganglion cells 1998;273(45):29626-34.
  2. Irwin N, Li YM, O'Toole JE, Benowitz LI. Proc Natl Acad Sci U S A Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth 2006;103:18320-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17114295
  3. Lorber B, Howe ML, Benowitz LI, Irwin N. Nat Neurosci Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways 2009;12:1407-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19855390.2770175
  4. Zai L, Ferrari C, Subbaiah S, Havton LA, Coppola G, Strittmatter S, Irwin N, Geschwind D, Benowitz LI. J Neurosci Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb 2009;29(25):8187-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19553458.
  5. Zai L, Ferrari C, Dice C, Subbaiah S, Havton LA, Coppola G, Geschwind D, Irwin N, Huebner E, Strittmatter SM, Benowitz LI. J Neurosci Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke 2011;31(16):5977-88. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21508223.3101108
  6. Kim D, Zai L, Liang P, Schaffling C, Ahlborn D, Benowitz LI. PLoS One Inosine enhances axon sprouting and motor recovery after spinal cord injury 2013;8:e81948. http://www.ncbi.nlm.nih.gov/pubmed/24312612.3846725

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